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    LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Lino Andreia C,Dang Van Duc,Lampropoulou Vicky,Welle Anna,Joedicke Jara,Pohar Jelka,Simon Quentin,Thalmensi Jessie,Baures Aurelia,Flühler Vinciane,Sakwa Imme,Stervbo Ulrik,Ries Stefanie,Jouneau Luc,Boudinot Pierre,Tsubata Takeshi,Adachi Takahiro,Hutloff Andreas,Dörner Thomas,Zimber-Strobl Ursula,de Vos Alex F,Dahlke Katja,Loh Gunnar,Korniotis Sarantis,Goosmann Christian,Weill Jean-Claude,Reynaud Claude-Agnès,Kaufmann Stefan H E,Walter Jörn,Fillatreau Simon Immunity B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention. 10.1016/j.immuni.2018.06.007
    Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nguyen Thi-Huong,Medvedev Nikolay,Delcea Mihaela,Greinacher Andreas Nature communications Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60-100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders. 10.1038/ncomms14945
    Role of IgE in autoimmunity. Sanjuan Miguel A,Sagar Divya,Kolbeck Roland The Journal of allergy and clinical immunology There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders. 10.1016/j.jaci.2016.04.007
    Bacterial Amyloids: The Link between Bacterial Infections and Autoimmunity. Nicastro Lauren,Tükel Çagla Trends in microbiology Molecular mimicry is a common mechanism used by many bacteria to evade immune responses. In recent years, it has become evident that bacteria also decorate the extracellular matrix (ECM) of their biofilms with molecules that resemble those of the host. These molecules include amyloids and other proteins, polysaccharides, and extracellular DNA. Bacterial amyloids, like curli, and extracellular DNA are found in the biofilms of many species. Recent work demonstrated that curli and DNA form unique molecular structures that are recognized by the immune system, causing activation of autoimmune pathways. Although a variety of mechanisms have been suggested as the means by which infections initiate and/or exacerbate autoimmune diseases, the mechanism remains unknown. In this article, we discuss recent work on biofilms that highlight the role of amyloids as a carrier for DNA and potentiator of autoimmune responses, and we propose a novel link between bacterial infections and autoimmune diseases. 10.1016/j.tim.2019.07.002
    Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Rosenzwajg Michelle,Lorenzon Roberta,Cacoub Patrice,Pham Hang Phuong,Pitoiset Fabien,El Soufi Karim,RIbet Claire,Bernard Claude,Aractingi Selim,Banneville Beatrice,Beaugerie Laurent,Berenbaum Francis,Champey Julien,Chazouilleres Olivier,Corpechot Christophe,Fautrel Bruno,Mekinian Arsène,Regnier Elodie,Saadoun David,Salem Joe-Elie,Sellam Jérémie,Seksik Philippe,Daguenel-Nguyen Anne,Doppler Valérie,Mariau Jéremie,Vicaut Eric,Klatzmann David Annals of the rheumatic diseases OBJECTIVE:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM:We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS:We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS:ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION:The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER:NCT01988506. 10.1136/annrheumdis-2018-214229